Hyposterolactone A, a 3α-Hydroxy Steroidal Lactone from the Deep-Sea-Derived Fungus Hypocrea sp. ZEN14.

Chemical investigation of the deep-sea-derived fungus Hypocrea sp. ZEN14 afforded a new 3α-hydroxy steroidal lactone, hyposterolactone A (1) and 25 known secondary metabolites (2-26). The structure of the new compound was established by detailed spectroscopic analysis, electronic circular dichroism (ECD) calculation as well as a J-based configuration analysis. Compound 10 showed potent cytotoxicity against Huh7 and Jurkat cells with IC50 values of 1.4 µM and 6.7 µM, respectively.

Anti-HIV Compounds from the Deep-Sea-Derived Fungus Chaetomium globosum.

Chemical investigation on the deep-sea-derived fungus Chaetomium globosum led to the isolation of nine compounds. By extensive analyses of the 1D and 2D NMR as well as HR-ESI-MS spectra, their structures were elucidated as xylariol A (1), 1,3-dihydro-4,5,6-trihydroxy-7-methylisobenzofuran (2), epicoccone B (3), epicoccolide B (4), chaetoglobosin G (5), chaetoglobosin Fex (6), cochliodone A (7), cochliodone B (8), and chaetoviridin A (9), assorting as four phenolics (1-4), two cytochalosans (5-6), and three azaplilones (7-9). Compounds 1-3 were firstly reported from C. globosum. Under the concentrations of 20 µg/mL, 1, 2, and 3 exhibited potent in vitro anti-HIV activity with the inhibition rates of 70 %, 75 %, and 88 %, respectively.

Discovery of andrastones from the deep-sea-derived Penicillium allii-sativi MCCC 3A00580 by OSMAC strategy.

Andrastones are unusual 6,6,6,5-tetracyclic meroterpenoids that are rarely found in nature. Previously, three andrastones were obtained from the rice static fermentation extract of the deep-sea-derived fungus Penicillium allii-sativi MCCC 3A00580. Inspired by one strain many compounds (OSMAC) approach, the oat static fermentation on P. allii-sativi was conducted. As a result, 14 andrastones were isolated by UV-guided isolation. The chemical structures of the nine new compounds (1-9) was established by comprehensive analysis of the NMR, MS, ECD, and X-ray crystallography and the five known ones (10-14) were assigned by comparing their NMR, MS, and OR data with those reported in literature. Compound 1 bears a novel hemiketal moiety while 2 is the first example to possess a novel tetrahydrofuran moiety via C-7 and C-15. All isolates were tested for anti-allergic bioactivity. Compound 10, 3-deacetylcitreohybridonol, significantly decreased degranulation with the IC50 value of 14.8 µM, compared to that of 92.5 µM for the positive control, loratadine. Mechanism study indicated 10 could decrease the generation of histamine and TNF-α by reducing the accumulation of Ca2+ in RBL-2H3 cells. These findings indicate andrastones could be potential to discover new anti-allergic candidate drugs.

Comparative Decellularization and Recellularization of Normal Versus Streptozotocin-Induced Diabetes Mellitus Rat Pancreas.

Decellularized (DC) organs/tissues offer a promising scaffold for regenerative bioengineering. However, it is not clear whether the diabetic mellitus (DM) pancreas can be used in decellularized and recellularized bioengineering. For assessment of these questions, murine pancreatic scaffolds of normal, type 1DM (T1DM) and type 2 DM (T2DM) pancreas were generated using a perfusion decellularization technique and assessed by histology, scanning electron microscopy, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). The capacity of DC pancreatic scaffolds to support attachment and proliferation of human umbilical vein endothelial cells (HUVECs) and MIN-6 ß cells was also assessed. Our results showed that DC pancreatic scaffolds were successfully produced from T1DM and T2DM pancreas and maintained their extracellular matrix (ECM) composition, 3D ultrastructure, and various cytokines. All of the pancreatic scaffolds were sufficiently cytocompatible and were able to support proliferation and adhesion of HUVECs and MIN-6 ß cells. The preliminary results support the biological utility of diabetes mellitus pancreatic scaffolds and pave the way for further investigations to assess the potential ability of using diabetes mellitus pancreas as scaffolds for recellularization and eventual medical applications.

[Genetic analysis and identification of candidate genes for a narrow leaf mutant (zy17) in rice].

Control of organ size by cell proliferation and cell expansion is a fundamental process in plant development, but little is known about the genetic and molecular mechanisms that determine organ size in plants. To understand the genetic and molecular mechanisms of organ growth control, we isolate a set of mutants with altered leaf size and identify the narrow leaf mutant, zhaiye 17 (zy17) (zhaiye means narrow leaf in Chinese). zy17 exhibits narrow leaves, slightly short plants, small panicles, reduced panicle branches and decreased grain numbers per panicle compared with the wild type. Our cytological analyses show that the narrow leaf phenotype of zy17 is caused by the reduced number of cells, indicating that ZY17 regulates cell proliferation. Genetic analyses show that the zy17 mutant phenotypes are controlled by a single gene. Using the whole genome resequencing approach and linkage analysis, we identify Os02g22390, Os02g28280 and Os02g29530 as candidate genes. Os02g22390 encodes a retrotransposon protein with the mutation occurring in the intronic region; Os02g28280 encodes a protein with unknown function with a base substitution resulting in non-synonymous mutation; Os02g29530 encodes a protein containing the PFAM domain related to glycosyltransferase, with a 2 bp deletion mutation causing a premature termination. Further studies on these three candidate genes will be helpful for understanding the molecular mechanism of organ size control in rice.

NrdH Redoxin enhances resistance to multiple oxidative stresses by acting as a peroxidase cofactor in Corynebacterium glutamicum.

NrdH redoxins are small protein disulfide oxidoreductases behaving like thioredoxins but sharing a high amino acid sequence similarity to glutaredoxins. Although NrdH redoxins are supposed to be another candidate in the antioxidant system, their physiological roles in oxidative stress remain unclear. In this study, we confirmed that the Corynebacterium glutamicum NrdH redoxin catalytically reduces the disulfides in the class Ib ribonucleotide reductases (RNR), insulin and 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), by exclusively receiving electrons from thioredoxin reductase. Overexpression of NrdH increased the resistance of C. glutamicum to multiple oxidative stresses by reducing ROS accumulation. Accordingly, elevated expression of the nrdH gene was observed when the C. glutamicum wild-type strain was exposed to oxidative stress conditions. It was discovered that the NrdH-mediated resistance to oxidative stresses was largely dependent on the presence of the thiol peroxidase Prx, as the increased resistance to oxidative stresses mediated by overexpression of NrdH was largely abrogated in the prx mutant. Furthermore, we showed that NrdH facilitated the hydroperoxide reduction activity of Prx by directly targeting and serving as its electron donor. Thus, we present evidence that the NrdH redoxin can protect against the damaging effects of reactive oxygen species (ROS) induced by various exogenous oxidative stresses by acting as a peroxidase cofactor.

Enhancing Corynebacterium glutamicum robustness by over-expressing a gene, mshA, for mycothiol glycosyltransferase.

Over-expression of the gene, mshA, coding for mycothiol glycosyl transferase improved the robustness of Corynebacterium glutamicum to various stresses. Intracellular mycothiol (MSH) content was increased by 114 % in WT(pXMJ19-mshA) compared to WT(pXMJ19). Survival rates increased by 44, 39, 90, 77, 131, 87, 52, 47, 57, 85 and 33 % as compared to WT(pXMJ19) under stress by H2O2 (40 mM), methylglyoxal (5.8 mM), erythromycin (0.08 mg ml(-1)), streptomycin (0.005 mg ml(-1)), Cd(2+) (0.01 mM), Mn(2+) (2 mM), formic acid (0.05 %), acetic acid (0.15 %), levulinic acid (0.25 %), furfural (7.2 mM), and ethanol (10 % v/v), respectively. Increased MSH content also decreased the concentration of reactive oxygen species in the presence of the above stresses. Our results may open a new avenue for enhancing robustness of industrial bacteria for production of commodity chemicals.

Precision therapy for intrahepatic cholangiocarcinoma: A case report on adjuvant treatment in a recurrent patient after surgery and literature review.

A 37-year-old female patient was diagnosed with intrahepatic cholangiocarcinoma (ICC), with the lesion located in the right lobe of the liver. Despite radical resection, postoperative adjuvant chemotherapy and a combination of adjuvant chemotherapy and immunotherapy, the patient continued to experience multiple instances of intrahepatic tumor metastases. Furthermore, the patient exhibited significant adverse reactions to systemic chemotherapy and had poor treatment tolerance. Guidance from paraffin section fluorescence in situ hybridization gene sequencing was used to select a combination of immunotherapy and targeted therapy treatments with programmed cell death 1 (PD-1)/PD-1 ligand 1 antibody durvalumab and the targeted drug pemigatinib. The patient tolerated the treatment and has continued to survive for 28 months. According to imaging evaluations, the lesions continued to decrease, with some disappearing completely. The tumor marker carbohydrate antigen 19-9 remained normal for >9 weeks during the treatment. This report described the patient's treatment process in detail and briefly reviewed relevant literature on the treatment progress of postoperative patients with ICC.

Taurocholic acid ameliorates hypertension through the activation of TGR5 in the hypothalamic paraventricular nucleus.

Diets rich in taurine can increase the production of taurine-conjugated bile acids, which are known to exert antihypertensive effects. Despite their benefits to the heart, kidney and arteries, their role in the central nervous system during the antihypertensive process remains unclear. Since hypothalamic paraventricular nucleus (PVN) plays a key role in blood pressure regulation, we aimed to investigate the function of bile acids in the PVN. The concentration of bile acids in the PVN of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKY) fed with normal chow was measured using LC-MS/MS, which identified taurocholic acid (TCA) as the most down-regulated bile acid. To fully understand the mechanism of TCA's functions in the PVN, bi-lateral PVN micro-infusion of TCA was carried out. TCA treatment in the PVN led to a significant reduction in the blood pressure of SHRs, with decreased plasma levels of norepinephrine and improved morphology of cardiomyocytes. It also decreased the number of c-fos+ neurons, reduced the inflammatory response, and suppressed oxidative stress in the PVN of the SHRs. Most importantly, the TGR5 receptors in neurons and microglia were activated. PVN infusion of SBI-115, a TGR5 specific antagonist, was able to counteract with TCA in the blood pressure regulation of SHRs. In conclusion, TCA supplementation in the PVN of SHRs can activate TGR5 in neurons and microglia, reduce the inflammatory response and oxidative stress, suppress activated neurons, and attenuate hypertension.

Nanoengineered Red Blood Cells Loaded with TMPRSS2 and Cathepsin L Inhibitors Block SARS-CoV-2 Pseudovirus Entry into Lung ACE2+ Cells.

The enzymatic activities of Furin, Transmembrane serine proteinase 2 (TMPRSS2), Cathepsin L (CTSL), and Angiotensin-converting enzyme 2 (ACE2) receptor binding are necessary for the entry of coronaviruses into host cells. Precise inhibition of these key proteases in ACE2+ lung cells during a viral infection cycle shall prevent viral Spike (S) protein activation and its fusion with a host cell membrane, consequently averting virus entry to the cells. In this study, dual-drug-combined (TMPRSS2 inhibitor Camostat and CTSL inhibitor E-64d) nanocarriers (NCs) are constructed conjugated with an anti-human ACE2 (hACE2) antibody and employ Red Blood Cell (RBC)-hitchhiking, termed "Nanoengineered RBCs," for targeting lung cells. The significant therapeutic efficacy of the dual-drug-loaded nanoengineered RBCs in pseudovirus-infected K18-hACE2 transgenic mice is reported. Notably, the modular nanoengineered RBCs (anti-receptor antibody+NCs+RBCs) precisely target key proteases of host cells in the lungs to block the entry of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), regardless of virus variations. These findings are anticipated to benefit the development of a series of novel and safe host-cell-protecting antiviral therapies.

Physiological roles of mycothiol in detoxification and tolerance to multiple poisonous chemicals in Corynebacterium glutamicum.

Mycothiol (MSH) plays important roles in maintaining cytosolic redox homeostasis and in adapting to reactive oxygen species in the high-(G + C)-content Gram-positive Actinobacteria. However, its physiological roles are ill defined compared to glutathione, the functional analog of MSH in Gram-negative bacteria and most eukaryotes. In this research, we explored the impact of intracellular MSH on cellular physiology by using MSH-deficient mutants in the model organism Corynebacterium glutamicum. We found that intracellular MSH contributes significantly to resistance to alkylating agents, glyphosate, ethanol, antibiotics, heavy metals and aromatic compounds. In addition, intracellular MSH is beneficial for withstanding oxidative stress induced by various oxidants in C. glutamicum. This study greatly expanded our current knowledge on the physiological functions of mycothiol in C. glutamicum and could be applied to improve the robustness of this scientifically and commercially important species in the future.

A study on aviation supply chain network controllability and control effect based on the topological structure.

The present paper focuses on the controllability of the aviation supply chain network and establishes the judgment criterion for structural controllability of the aviation supply chain network. We determine the control effect by applying the control input to different nodes in the aviation supply chain network. These control nodes include the core enterprises of the aviation supply chain network, the upstream suppliers, and the downstream distributors. It is observed that the control effect is better when the control input is applied to the upstream suppliers of the aviation supply chain network than to the core enterprises of the aviation supply chain network. It is also more desirable to apply the control input to the core enterprises than to the distributors. That is, the control effect is the weakest when the control input is applied to the distributors, whereas the effect is best on application of the control to the upstream suppliers in the supply chain (that is, by choosing the upstream suppliers as the controlled nodes in the aviation supply chain network).

Reducing the Excess Activin Signaling Rescues Muscle Degeneration in Myotonic Dystrophy Type 2 Drosophila Model.

Expanded non-coding RNA repeats of CCUG are the underlying genetic causes for myotonic dystrophy type 2 (DM2). There is an urgent need for effective medications and potential drug targets that may alleviate the progression of the disease. In this study, 3140 small-molecule drugs from FDA-approved libraries were screened through lethality and locomotion phenotypes using a DM2 Drosophila model expressing 720 CCTG repeats in the muscle. We identified ten effective drugs that improved survival and locomotor activity of DM2 flies, including four that share the same predicted targets in the TGF-ß pathway. The pathway comprises two major branches, the Activin and BMP pathways, which play critical and complex roles in skeletal development, maintenance of homeostasis, and regeneration. The Drosophila model recapitulates pathological features of muscle degeneration in DM2, displaying shortened lifespan, a decline in climbing ability, and progressive muscle degeneration. Increased levels of p-smad3 in response to activin signaling were observed in DM2 flies. Decreased levels of activin signaling using additional specific inhibitors or genetic method ameliorated climbing defects, crushed thoraxes, structure, and organization of muscle fibers. Our results demonstrate that a decrease in activin signaling is sufficient to rescue muscle degeneration and is, therefore, a potential therapeutic target for DM2.

Metabolic tuning of a stable microbial community in the surface oligotrophic Indian Ocean revealed by integrated meta-omics.

Understanding the mechanisms, structuring microbial communities in oligotrophic ocean surface waters remains a major ecological endeavor. Functional redundancy and metabolic tuning are two mechanisms that have been proposed to shape microbial response to environmental forcing. However, little is known about their roles in the oligotrophic surface ocean due to less integrative characterization of community taxonomy and function. Here, we applied an integrated meta-omics-based approach, from genes to proteins, to investigate the microbial community of the oligotrophic northern Indian Ocean. Insignificant spatial variabilities of both genomic and proteomic compositions indicated a stable microbial community that was dominated by Prochlorococcus, Synechococcus, and SAR11. However, fine tuning of some metabolic functions that are mainly driven by salinity and temperature was observed. Intriguingly, a tuning divergence occurred between metabolic potential and activity in response to different environmental perturbations. Our results indicate that metabolic tuning is an important mechanism for sustaining the stability of microbial communities in oligotrophic oceans. In addition, integrated meta-omics provides a powerful tool to comprehensively understand microbial behavior and function in the ocean. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-021-00119-6.

A facile macroporous resin-based method for separation of yellow and orange Monascus pigments.

The yellow Monascus pigments (YMPs) named monascin and ankaflavin and the orange Monascus pigments (OMPs) named rubropunctatin and monascorubrin are two groups of bioactive components in a mixture state in the Monascus fermented products. In order to separate these two groups of bioactive pigments, a facile macroporous resin-based method was developed. The weak-polar resin CAD-40 was selected from the seven tested macroporous resins as it revealed better properties for the adsorption and desorption of the YMPs and OMPs. Then, CAD-40 resin was used for column-chromatographic separation. After eluted by 4 bed volumes of ethanol, the yellow group (monascin and ankaflavin) and the orange group (rubropunctatin and monascorubrin) were successfully separated and purified, with an increased content from 49.3% and 44.2% in the crude pigment extract to 85.2% and 83.0% in the final products, respectively. This method would be helpful for the large-scale separation and purification of Monascus pigment products with specific bioactivity.

Homoeologous nonreciprocal recombination in polyploid cotton.

Polyploid formation and processes that create partial genomic duplication generate redundant genomic information, whose fate is of particular interest to evolutionary biologists. Different processes can lead to diversification among duplicate genes, which may be counterbalanced by mechanisms that retard divergence, including gene conversion via nonreciprocal homoeologous exchange. Here, we used genomic resources in diploid and allopolyploid cotton (Gossypium) to detect homoeologous single nucleotide polymorphisms provided by expressed sequence tags from G. arboreum (A genome), G. raimondii (D genome) and G. hirsutum (AD genome), allowing us to identify homoeo-single nucleotide polymorphism patterns indicative of potential homoeologous exchanges. We estimated the proportion of contigs in G. hirsutum that have experienced nonreciprocal homoeologous exchanges since the origin of polyploid cotton 1-2 million years ago (Mya) to be between 1.8% and 1.9%. To address the question of when the intergenomic exchange occurred, we assayed six of the genes affected by homoeo-recombination in all five Gossypium allopolyploids using a phylogenetic approach. This analysis revealed that nonreciprocal homoeologous exchanges have occurred throughout polyploid divergence and speciation, as opposed to saltationally with polyploid formation. In addition, some genomic regions show multiple patterns of homoeologous recombination among species.

[The mechanism of DNA damage checkpoint control].

DNA damage caused by many factors may lead to missense mutation, deletion or illegal recombination. To maintain genomic integrity, cells have evolved complex surveillance mechanisms termed cell cycle checkpoint. DNA damage checkpoint composed of various checkpoint-related proteins can sense DNA damage and execute cell cycle arrest through different signaling transduction pathway involving protein kinase cascades, thereby allowing time for cells to repair the damaged DNA.

[Transcatheter closure of perimembranous ventricular septal defects in children following transthoracic echocardiography].

OBJECTIVE: To evaluate the efficacy and safety of transcatheter closure of perimembranous ventricular septal defects (VSD) in children following transthoracic echocardiography (TTE). METHODS: From September 2002 to December 2005, eighty-nine children (47 males and 42 females) with perimembranous (VSD) underwent an attempt of transcatheter interventional occlusion. Among the 89 children, one of them was diagnosed with patent ductus arterious (PDA) and six with VSD leakage after the surgical repair (three with leakage after the surgical repair of tetralogy of Fallot and three with leakage after the surgical repair of VSD). The mean age of patients was (6.4 +/- 3.9) years (ranged from 1 to 18 years). The mean body weight of patients was (22 +/- 11 )kg (ranged from 9 to 78 kg). The mean diameter of VSD measured by TTE was (4.3 +/- 1.5) mm(ranged from 2 to 8.5mm). The path of artery to vein was established following X-rays and TTE. Occluder was released through the right heart system. All patients were followed up in 1, 3, 6 and 12 months after procedure of TTE, X-ray and electrocardiography. RESULT: The devices were deployed successfully in 85 patients, the rate of success was 95.5%. No death occurred during and after the procedure. There was trivial residual shunt in 12 patients immediately after the closure by TTE and angiography. Twenty-four hours later, only 3 patients had trivial residual and no shunt existed after 6 months follow-up. Convulsion occurred in 1 case due to serious cardiac arrhythmias. Hemolysis was found in 2 cases. Other complications included 2 cases of complete left bundle branch block, 1 cases of left anterior fascicular block and 3 cases of incomplete right bundle branch block. They recovered after 3 to 7 days of corticosteroid treatment. After 1 to 36 months (mean 9 months) follow-up, none of occluders displacement occurred and no valve was involved. CONCLUSION: Transcatheter closure of membranous VSD using occluder would be safe and effective for children, and the results of short-term was satisfied. Transcatheter closure of VSD following TTE is a feasible method. TTE has the potential benefit of avoiding general anesthesia and esophageal intubation in children.

[Effects of two metabolites of cultured marine fungus, Halorosellinia oceanicum 323, on the contraction of isolated guinea-pig ileum].

AIM: To investigate the effects of 323-A and 323-B, two isomers extracted from the metabolites of cultured marine fungus, Halorosellinia oceanicum 323, on the contraction of isolated guinea pig ileum (GPI). METHODS: The GPI contractions were recorded with a two-channel-physiological recorder with tension transducers. Cumulative dose-response curves of contractions of isolated GPI induced by histamine (Hist), acetylcholine (ACh) and potassium chloride (KCl) were constructed, then the influences of 323-A and 323-B on each curve were observed. Furthermore, possible mechanisms underlying effects of the two compounds were explored by analyzing their influences on the biphasic contractile response to ACh, with comparison of a calcium antagonist, verapamil (Ver). RESULTS: The data indicated that both 323-A and 323-B inhibited the contractile actions of GPI triggered by Hist, ACh and KCl in a concentration-dependent manner, with pD2' values of 5.13, 4.97, 5.36 and 5.51, 5.56, 5.62, respectively. The initial phase component of the ACh-elicited contractions, in the absence of external Ca2+, was significantly reduced by 323-A, 323-B, as well as Ver, whereas the subsequent sustained tonic contractions induced by adding Ca2+ to the bath solution were almost unaffected. CONCLUSION: These results suggest that 323-A and 323-B have calcium antagonistic effects similar to that of Ver in mechanisms, and they might have potential to be developed as calcium antagonists.

[Digital anatomy of the perforator flap in the thigh].

OBJECTIVE: To provide algorithmic morphological data that enables safe elevation of the flow-through perforator flap, chimeric perforator flap in the thigh. METHODS: 15 fresh cadavers were injected with a modified lead oxide-gelatin mixture for three-dimensional reconstruction using a spiral computed tomography scanner and specialized volume-rendering software (MIMICS). All of specimens were then dissected by layers. Angiography and photography were used to document the precise course, size, location, and type of individual perforators in the thigh region. The surface areas of cutaneous territories and perforator zones were measured and calculate with Photoshop and Scion Image. RESULTS: The main artery supplying the thigh is femoral artery. There are (41 +/- 4.0) perforators whose outer diameters > or = 0.5 mm. These perforators have a superficial pedicle length of (4.2 +/- 1.7) cm. The average outer diameter is (0.8 +/- 0.1) mm. Each perforator supplies an average area of (44 +/- 6.4) cm2. There are lots of truly anastomoses among perforaors to form a subcutaneous network in the thigh. CONCLUSIONS: The volume rendering technique is very useful for showing the subcutaneous network and preoperative flap design. The thigh appears to have the greatest potential for harvesting new or modified perforator flaps, especially, flow-through perforator flap or chimeric perforator flap.